This application is related to U.S. patent application Ser. No. 09/361,553, entitled xe2x80x9cAbsorbable Brachytherapy and Chemotherapy Delivery Devices and Methods,xe2x80x9d to William G. Mavity, Robert A. Stern, Shigemasa Osaki and Paul O. Zamora, filed on Jul. 27, 1999, and the specification thereof is incorporated herein by reference.
1. Field of the Invention (Technical Field)
This invention relates to methods, devices and systems for radiation delivery devices and combination radiation and drug delivery devices, and particularly methods, devices and systems for absorbable radiation delivery devices and combination radiation and drug delivery devices having elements that will be absorbed in tissue over time.
2. Background Art
Note that the following discussion refers to a number of publications by authors and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
A number of techniques have been utilized or proposed to treat tumor growth, including radiation therapy, chemotherapy, and other treatment modalities. Brachytherapy, a form of radiation therapy, relies on implanting a radiation source in the body to provide localized treatment, as contrasted, for example, with treating a site from a distance by external beam radiation. In prostate brachytherapy, radiation is delivered by small xe2x80x9cseedsxe2x80x9d placed within the area being treated. Such placement minimizes the risk of affecting nearby tissue, while still delivering adequate radiation to destroy diseased cells.
In general, radioactive materials such as palladium-103 (Pd-103) and iodine-125 (I-125) are used, which have a relatively short half-life and emit low energy X-rays. A variety of different types of brachytherapy devices have been used to treat cancer and various types of tumors in human or animal bodies. Art conventional brachytherapy devices are contained in small metal capsules, generally made of titanium or stainless steel, and are welded or use adhesives to seal in the radioactive material.
The art conventional brachytherapy devices generally cannot be removed after placement. Thus they remain in the body even after the effective radiation dose has been delivered. The presence of these metallic brachytherapy devices can interfere with subsequent diagnostic X-rays or other imaging modalities, since they are radiopaque. In addition, these brachytherapy devices can interfere with other treatment modalities, such as thermal ablation or external beam radiation. Further, metallic brachytherapy devices are generally of a different density than that of the tissue in which they are placed, and can migrate after placement, both while still effectively emitting therapeutic radiation or after the radioactive source has decayed. Thus the devices may enter the lymphatic system or otherwise move to a position within the body that may cause medical complications, potential diagnostic confusion and the like.
One type of conventional brachytherapy device 1 is shown in FIG. 1, in which the device 1 contains a therapeutic amount of a radioisotope 2 disposed in a carrier 3. The radioisotope-containing carrier 3 is in a cavity 5 of a cylindrical casing 4. Casing 4, made of a metal such as stainless steel or titanium, is sealed at ends 6 and 7, typically by welding.
Another type of conventional brachytherapy device 10, disclosed in U.S. Pat. No. 4,891,165, is shown in FIG. 2 and employs two metal sleeves 12 and 14. Each of the sleeves has one closed end 16 and 18, with sleeve 14 having an outer diameter that is smaller than the inner diameter of the sleeve 12, permitting the sleeve 14 to slide inside sleeve 12. A radioactive source, such as pellets, can be placed inside the smaller sleeve 14, and then the larger external sleeve 12 slid over the smaller sleeve 14. The brachytherapy device 10 is permanently sealed, such as by welding.
Another conventional brachytherapy device 30, disclosed in U.S. Pat. No. 4,784,116, is shown in FIG. 3 and uses a single metal tube 32 which has metal end caps 34 and 36 inserted at the ends 38 and 40. The tube 30 contains the radioactive source. The ends 38 and 40 are welded, or adhesively secured, to the end caps 34 and 36 to seal the brachytherapy device 30.
Yet another conventional brachytherapy device 50, disclosed in U.S. Pat. No. 5,683,345, is shown in FIG. 4, has metal end plugs 52 and 54 that are slid into the open ends of a metal tube 56. The end plugs 52 and 54 are adhesively fixed and the metal of tube 56 then bent around the end plugs 52 and 54, or the end plugs 52 and 54 are welded to the tube 56.
Another conventional brachytherapy device 70 is shown in FIG. 5, which employs a metal tube 72 with ends 74 and 76. One end 74 of the tube 72 is welded, forming a metal weld bead 78 sealing the end 74. After placement of the radioactive material, the end 76 is welded forming metal bead 80 closing off end 76.
Yet another metal brachytherapy device 90, disclosed in U.S. Pat. No. 6,132,359, is shown in FIG. 6, which depicts metal case 94 with a center portion 96 and two end portions 98, and containing a radioactive source 92. Device 90 may be made by swaging one end portion 98 of casing 94, then welding swaged end portion 98 to provide a weld seal 100. After placement of the radioactive source 92 within the case 94, the second end portion 98 of casing 94 is then swaged and welded to provide a weld seal 102. While this configuration is purported to provide a more uniform radiation dose, it still utilizes a permanently-placed metal device.
Each of the foregoing devices is expensive and difficult to manufacture, involving a very precise welding step on a highly radioactive component, requiring shielding, robotics and other complex steps. In addition, quality control on such radioactive metal sources is difficult and time consuming.
The preparation of biodegradable radioactive materials is described in U.S. Pat. Nos. 5,256,765 and 5,194,581. In these materials, a radioisotope may be bound to a biodegradable polymeric matrix where the purpose is usually to provide for controlled release of the radioactive material over time. Such biodegradable radioactive materials are generally not useful for brachytherapy since they release the radioactive material rather than localize it at the desired treatment site.
In another approach, disclosed in co-pending and co-owned application Ser. No. 09/361,553, a radiation delivery component and a drug delivery component immobilized on a bioabsorbable structure is disclosed. The bioabsorbable structure has a predefined persistence period, such that it will remain sufficiently intact after implantation at a target site in patient tissue so that it can localize or sequester the radionuclide at the target site for a minimum threshold time, and further release or disperse the drug, which may be a chemotherapeutic agent, over a complimentary time. The minimum threshold time will usually depend at least in part on the half-life of the radionuclide. In particular, the predetermined persistence period of the bioabsorbable structure will usually be substantially longer than the half-life of the radionuclide, usually being at least two times longer, preferably being at least four times longer, and often being at least ten times longer. In this way, the radionuclide is not released from the bioabsorbable structure until after the persistence period has passed, so that the maximum effect of the radiation is limited to the target, and potential systemic or clearance organ dosage to the patient is below a known or predicted level of safety.
The use of biodegradable or bioerodible materials to provide sustained or controlled release of chemotherapeutic or other drugs, including bioactive drugs, has been known for a number of years. Biodegradable implants for the controlled release of hormones, such as contraceptive hormones, were developed over twenty years ago, and have been used as birth control devices. Biodegradable or bioerodible materials employed for controlled release of drugs include polyanhydrides, polyglycolic acid, polylactic/polyglycolic acid copolymers, polyhydroxybutyrate-valerate and other aliphatic polyesters, among a wide variety of polymeric substrates employed for this purpose. Biodegradable implantable materials, some of which have been used in drug delivery systems, are described in U.S. Pat. Nos. 5,656,297; 5,543,158; 5,484,584; 4,897,268; 4,883,666; 4,832,686; and 3,976,071. U.S. Pat. No. 5,876,452 describes biodegradable polymeric material, such as polyanhydries and aliphatic polyesters, providing substantially continuous release of bioactive drugs, including bi-phasic release of bioactive drugs.
The synergistic effect of combined radiation and chemotherapy has long been appreciated, and is a standard modality of cancer therapy. Prior art methods have frequently employed systemic chemotherapy, where chemotherapy drugs are administered intravenously, orally or by other systemic means, and external radiotherapy is employed, such as external beam radiation. In one instance, biodegradable polymer implants for the treatment of cancer, containing the cancer chemotherapeutic drug carmustine, have been used with concurrent external beam radiation, and found to increase survival in patients with metastatic brain tumors. (Ewend M G, Williams J A, Tabassi K, et al. Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. Cancer Res 1996; 56(22):5217-5223) Conventional systemically administered chemotherapeutic agents have also been used in conjunction with implanted brachytherapy devices.
The present invention is directed to a brachytherapy device for use in radiation treatment of an affected tissue region. In one embodiment, the brachytherapy device includes a radioactive material including a radioisotope and a sealed bioabsorbable polymeric housing containing the radioactive material. Thus the bioabsorbable polymeric housing may be of any shape or configuration, and may be made by any means known in the art, so long as it contains the radioactive material. In one embodiment, the bioabsorbable polymeric housing for containing the radioactive material is formed by at least one tube having an axis and two ends, with the at least one tube being sealed at each end. Where the bioabsorbable polymeric housing is a tube or tube-like structure with at least one end, it may further include bioabsorbable polymeric material fixed in each end of the tube.
The device may further include a radiopaque medium, which may be disposed on at least a portion of the external surface of the bioabsorbable polymeric housing, such as a tube, may be disposed within at least a portion of the structure of the bioabsorbable polymeric housing, such as a tube, or may be disposed within the radioactive material.
The radioactive material of the device may include a chelate which is chelated to the radioisotope. The chelate, particularly for Pd-103, may be a porphine or a porphyrin. Applicable radioisotopes include Pd-103 and I-125. The radioactive material may further include a bioabsorbable substrate, which may be a a fatty acid such as palmitic acid, lauric acid or myristic acid. In one embodiment, the bioabsorbable substrate has a melting temperature above about 40xc2x0 C. but below the melting temperature of the bioabsorbable polymeric housing.
The bioabsorbable polymeric housing may be made from a biocompatible polymeric material such as polycaprolactone, poly(D,L-lactide) poly(L-lactide), polyglycolide, poly(dioxanone), poly(glycolide-co-trimethylene carbonate), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(L-lactide-co-D,L-lactide) or poly(glycolide-co-trimethylene carbonate-co-dioxanone). In one embodiment, the persistence of the bioabsorbable polymeric housing within a living organism is in excess of ten half-lives of the radioisotope.
The device may further include an effective amount of a therapeutic drug which may be disposed on at least a portion of the external surface of the bioabsorbable polymeric housing, such as a tube, or may be disposed within at least a portion of the structure of the bioabsorbable polymeric housing, such as a tube. The therapeutic drug may be one or more radiosensitizer drugs, chemotherapeutic drugs, anti-angiogenesis drugs, hormones, or apoptosis inducing drugs. The device may also include one or more coating constituents admixed with the therapeutic drug, which may assist in adhering the therapeutic drug to the device, control the rate of release of the therapeutic drug or provide similar functions.
The invention further provides a method for radiation treatment of an affected tissue region in a patient, which method includes the steps of obtaining a radioactive material comprising a radioisotope, fabricating a bioabsorbable polymeric housing to contain the radioactive material, the housing being formed by at least one tube having an axis and two ends, placing the radioactive material within the at least one tube comprising the polymeric housing, and placing the polymeric housing containing the radioactive material in the affected tissue region of the patient. In this method, any of the components of the device described herein may be employed.
The invention further provides a method of manufacturing a brachytherapy device for use in the radiation treatment of an affected tissue region, which method includes the steps of providing a radioactive material, fabricating a bioabsorbable polymeric housing to contain the radioactive material, the housing being formed by at least one tube having an axis and two ends, and placing the radioactive material within the at least one tube comprising the polymeric housing. Such method may further include the steps of sealing one end of the at least one tube prior to placing the radioactive material within the at least one tube and sealing the remaining end of the at least one tube subsequent to placing the radioactive material within the at least one tube. In this method, any of the components of the device described herein may be employed.
The invention thus provides methods and devices for the delivery of localized radioactivity, and preferably also concurrent delivery of localized chemotherapeutic, bioactive or other drugs to patients for therapeutic purposes. These improved delivery devices deliver local radiation, and optionally local chemotherapeutic or bioactive drugs, and are degradable after implantation so that the devices largely or completely disappear from the treatment region over time. The outer surface of such devices, however, have sufficient permanence or persistence so that the radioactive source material remains localized at the site of implantation at all times while the emitted radiation remains significant. Fabrication methods and techniques permit the construction of brachytherapy devices having a variety of forms, including devices sized the same as art conventional devices commonly used in brachytherapy.
The brachytherapy devices of this invention contain surfaces that can be easily coated with any of a variety of polymers, matrixes, coatings, eluting surfaces and the like. Because art conventional brachytherapy devices are metal, primarily stainless steel or titanium, the surface coatings which may be employed are limited by the metal substrate. There are a variety of coatings and the like known in the art which may be employed with polymeric materials. U.S. Pat. No. 5,338,770 describes methods and materials for coating biomedical devices and implants with poly(ethylene oxide) chains suitable for covalent attachment of bioactive molecules intended to counteract blood-material incompatibility. U.S. Pat. No. 5,463,010 describes membranes, including polymerized aliphatic hydrocyclosiloxane monomers, for use in coating biomedical devices and implants, and suitable for use as a substrate for covalent attachment of other molecules. U.S. patent application Ser. No. 09/098,072 describes methods useful in the present invention for coating polymeric and other materials. The full disclosures of each of these patents and pending application are incorporated herein by reference.
Accordingly, it is an object of this invention to provide a biocompatible and bioabsorbable brachytherapy source and device for use in treatment of disease, including radiation therapy of cancers.
It is a further object of this invention to provide a method for brachytherapy utilizing a source and device which approximates the size and shape of current art metal devices, and which may be similarly used and placed within a patient, but which are made of a bioabsorbable substance, and are absorbed into the body subsequent to substantial decay of the radiation.
It is further an object of this invention to provide a brachytherapy source and device in which the housing is not metallic, and minimally shields the effective dissemination of radiation, providing optimal radiation dosimetry to the tissues to be treated.
It is a further objection of this invention to provide a biocompatible and bioabsorbable brachytherapy source, including a sealed case and a radioactive component complex, wherein the radioactive component complex is biocompatible, and preferably bioabsorbable.
Other objects, advantages and novel features, and further scope of applicability of the present invention will be set forth in part in the detailed description to follow, taken in conjunction with the accompanying drawings, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.